Diazo ketones formation

Diazo ketone cyclizathn. Some years ago Mander and his group1 demonstrated that the protonated diazomethylcarbonyl group can initiate cyclizations in unsaturatcd systems. In the case of phenolic diazo ketones, formation of spirodienones can predominate over competing side reactions (dienone-phenol rearrangement). Tetra-fluoroboric acid or boron trifluoride etherate can be used, but trifluoroacetic acid is usually the acid of choice. 

More definitive evidence for the formation of an oxirene intermediate or transition state was presented recently by Cormier 80TL2021), in an extension of his earlier work on diazo ketones 77TL2231). This approach was based on the realization that, in principle, the oxirene (87) could be generated from the diazo ketones (88) or (89) via the oxocarbenes 90 or 91) or from the alkyne (92 Scheme 91). If the carbenes (90) (from 88) and (91) (from 89) equilibrate through the oxirene (87), and if (87) is also the initial product of epoxidation of (92), then essentially the same mixture of products (hexenones and ketene-derived products) should be formed on decomposition of the diazo ketones and on oxidation of the alkyne this was the case. 

An extensive series of low-temperature matrix isolation experiments has failed to provide any evidence of oxirene formation, either by diazo ketone photolysis (82CB2192) or by attempted photo-retro-cycloaddition (82CB2202). 

An a-diazo ketone 1 can decompose to give a ketocarbene, which further reacts by migration of a group R to yield a ketene 2. Reaction of ketene 2 with water results in formation of a carboxylic acid 3. The Woljf re arrangement is one step of the Arndt-Eistert reaction. Decomposition of diazo ketone 1 can be accomplished thermally, photochemically or catalytically as catalyst amorphous silver oxide is commonly used ... 

The ketocarbene 4 that is generated by loss of Na from the a-diazo ketone, and that has an electron-sextet, rearranges to the more stable ketene 2 by a nucleophilic 1,2-shift of substituent R. The ketene thus formed corresponds to the isocyanate product of the related Curtius reaction. The ketene can further react with nucleophilic agents, that add to the C=0-double bond. For example by reaction with water a carboxylic acid 3 is formed, while from reaction with an alcohol R -OH an ester 5 is obtained directly. The reaction with ammonia or an amine R -NHa leads to formation of a carboxylic amide 6 or 7 ... 

This silyl hydrazone formation-oxidation sequence was originally developed as a practical alternative to the synthesis and oxidation of unsubstituted hydrazones by Myers and Furrow [31]. The formation of hydrazones directly from hydrazine and ketones is invariably complicated by azine formation. In contrast, silyl hydrazones can be formed cleanly from /V,/V -bis(7< rt-butyldimethylsilyl)hydrazine and aldehydes and ketones with nearly complete exclusion of azine formation. The resulting silylhydrazones undergo many of the reactions of conventional hydrazones (Wolff-Kishner reduction, oxidation to diazo intermediate, formation of geminal and vinyl iodides) with equal or greater efficiency. It is also noteworthy that application of hydrazine in this setting may also have led to cleavage of the acetate substituents. 

FORMATION AND PHOTOCHEMICAL WOLFF REARRANGEMENT OF CYCLIC a-DIAZO KETONES D-NORANDROST-5-EN-3 -0L-16-CARB0XYLIC ACIDS, 52, 53 FORMIC ACID, AZIDO—, tert-BUTYL ESTER, 50, 9 Formylation, with acetic formic anhydride, 50, 2 p-FORMYLBENZENESULFONAMIDE, ... 

FORMATION AND PHOTOCHEMICAL WOLFF REARRANGEMENT OF CYCLIC a-DIAZO KETONES D-NORANDROST-5-EN-3P-OL-16-CARBOXYLIC ACIDS... 

In all of the examples cited in Section 1.2.2.3.2.3.1, the diazo compounds are arranged such that none has a 3-hydride available. It could be expected that if a simple a-diazo ketone with fi-C — H bonds were exposed to the rhodium catalyst, metallocarbene formation would proceed as usual, but that /S-hydride elimination would compete with the desired 1,5-insertion. Such a /3-hydride elimination could, in fact, be viewed as a 1,2-insertion, i.e., 1 to 2. 

In recent work67, it has been demonstrated that simple a-diazo ketones and esters can, in fact, be induced to undergo 1,5-insertion in preparatively useful yields. It was already known51 that in the rhodium-catalyzed insertion process, methyl C-H is electronically less reactive than methylene C-H or methine C-H. It therefore seemed likely that competing -hydride elimination would be least likely with a diazoethyl ketone. Indeed, on cyclization of 2-diazo-3-tetrade-canone, only a trace of the enone product from /J-hydride elimination is observed. The predominant side reaction competing with 1,5-insertion is dimer formation. 

A neutral diazo compound can be considered as both a nucleophile and an electrophile. Thus, it can be substituted by the combination of an electrophilic moiety and a nucleophilic moiety (X+ Nu ") (Scheme 8). In practice, the diazomethyl group is transformed to the fluoromethyl group by treatment with hydrogen fluoride/pyridine mixture (70 30 w/w) (X = H Nu = F), or to the halofluoromethyl group by addition of A-halosuccinimide in the same medium (X = Cl, Br, I Nu = F), e.g. formation of l.16 The reaction can be performed on secondary diazo alkanes, diazo ketones or diazo esters.16 90 316... 

Disadvantages of the silver-promoted method for Amdt-Eistert homologation are the large excess of nucleophile required and also the requirement for the use of the free amine during peptide formation procedures. 13 Activation of the diazo ketone by UV light has been shown to be suitable for this type of procedure and good yields are obtained using only 1.2 equivalents of a hydrochloride salt of an amino ester in the presence of triethylamine (Scheme 5). 14 ... 

Solid-Phase Synthesis of (53-Peptides Reaction of Fmoc-Protected Diazo Ketones with Concomitant (53-Peptide Formation on a Solid Support 1401... 

Peptidyl bromomethyl ketones (Scheme 2) are synthesized by the same method used to prepare chloromethyl ketones (Scheme 1) namely, the reaction of peptidyl diazomethyl ketones with HBr. 16-18 This reaction proceeds readily for either chloromethyl or bromomethyl ketones, although a contaminant, the N-methylated compound, is usually observed in the final reaction product. 1 A variation of this method involves the use of LiBr, which facilitates the formation of acid-sensitive protected amino acids. 1 As with the chloromethyl synthesis, only Z and Boc should be used to protect the amino acids. 3 Although the reaction of diazo ketones with HBr is well known and relatively simple, only a few compounds have been synthesized (Table 2). 

A similar transformation was observed with the rhodium trifluoroacetate catalyzed decomposition of diazo ketones in the presence of benzene (Scheme 32).130 The cycloheptatrienes (147) formed in this case were acid labile and could be readily rearranged to benzyl ketones (148) on treatment with TFA. The reaction was effective even when the side chain contained reactive halogen and cyclopropyl functionality, but competing intramolecular reactions occurred with benzyl diazomethyl ketone. A more exotic example of this reaction is the rhodium(ll) trifluoroacetate catalyzed decomposition of the diazopenicillinate (149) in the presence of anisole, which resulted in the formation of two cycloheptatriene derivatives (150) and (151) (equation 35).m... 

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